Drug combinations have been shown to have several advantages compared to treatment with a single therapeutic agent, including potential synergistic effects, fewer occurrences of drug resistance, and enhanced efficacy. Greco F, Vicent Ma. Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Advanced drug delivery reviews. 2009; 61(13):1203-13. The importance of drug combinations can be seen in applications ranging from treatment of cancer and HIV/AIDS to multi-drug resistant bacterial infections. Mayer L, Janoff A. Optimizing combination chemotherapy by controlling drug ratios. Molecular interventions. 2007; 7(4):216-23, Sosnik A, Chiappetta D, Carcaboso A. Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead. Journal of controlled release: official journal of the Controlled Release Society. 2009; 138(1):2-15, and Wu P, Grainger D. Drug/device combinations for local drug therapies and infection prophylaxis. Biomaterials. 2006; 27(11):2450-67. However, combining multiple drugs into a single treatment requires careful optimization to enhance therapeutic effects beyond that of a singular drug. Co-delivery of certain drug combinations may require novel delivery vehicles capable of combining hydrophilic and hydrophobic drugs, actively targeting certain cell populations, and controlling the temporal release of both drugs independently. Sengupta S, Eavarone D, Capila I, Zhao G, Watson N, Kiziltepe T, et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature. 2005; 436(7050):568-72. Zhang L, Radovic-Moreno A, Alexis F, Gu F, Basto P, Bagalkot V, et al. Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates. Chem Med Chem. 2007; 2(9):1268-71. Developments in nanotechnology, such as particles and other delivery systems, present a new arena for overcoming these and other challenges associated with combination drug delivery.
Co-delivery is relevant to many topical delivery systems that target delivery of pharmaceutical agents either externally, such as to the skin or eye, or internally, such as to the mucous membranes of the mouth, vagina or rectum. Topical delivery is advantageous in that it avoids first pass metabolism, is convenient for and generally accepted by users, presents the opportunity for easily reversible treatment and may have smaller dosing requirements. Prausnitz M, Langer R. Transdermal drug delivery. Nature biotechnology. 2008; 26(11):1261-8, Madhav N, Shakya A, Shakya P, Singh K. Orotransmucosal drug delivery systems: a review. Journal of controlled release: official journal of the Controlled Release Society. 2009; 140(1):2-11. Advances in topical delivery systems have yielded success with transdermal delivery of contraceptives, medical fabrics loaded with antibiotics for more effective wound healing, and buccal delivery of an anti-Alzheimer's drug. Burkman R. The transdermal contraceptive system. American journal of obstetrics and gynecology. 2004; 190(4 Suppl):53, Huang Z-M, He C-L, Yang A, Zhang Y, Han X-J, Yin J, et al. Encapsulating drugs in biodegradable ultrafine fibers through co-axial electrospinning. Journal of biomedical materials research Part A. 2006; 77(1):169-79, and Kapil R, Dhawan S, Beg S, Singh B. Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation. Drug development and industrial pharmacy. 2013; 39(3):466-80. Novel delivery vehicles have expanded the potential to deliver more diverse drugs in a variety of applications. For example, dissolving microneedles made of polysaccharides developed by Lee et al. have allowed for precisely tuned delivery of both small molecules and biologics transdermally. Lee J, Park J-H, Prausnitz M. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008; 29(13):2113-24. das Neves et al. have developed mucosal-penetrating nanoparticles for the delivery of antiretrovirals to the vagina as HIV pre-exposure prophylaxis. das Neves J, Michiels J, Arien K, Vanham G, Amiji M, Bahia M, et al. Polymeric nanoparticles affect the intracellular delivery, antiretroviral activity and cytotoxicity of the microbicide drug candidate dapivirine. Pharmaceutical research. 2012; 29(6):1468-84. The expansion of deliverable drugs via topical delivery is permitted by the development of novel delivery systems that overcome the challenges associated with topical delivery, such as drug limitations based on solubility, particle size, molecular weight and polymorphism. However, delivery of drug combinations using topical systems has been largely unexplored due to a number of challenges associated with co-delivery, including delivery of physicochemically diverse drugs and difficulty in controlling independent release rates.